| Abstrakt: |
Atypical antipsychotic drugs (APDs) such as clozapine and olanzapine antagonize both D1 and D2 receptors; however, little is known regarding their pharmacologic effect on specific neuronal elements within the local circuitry of corticolimbic regions, such as medial prefrontal cortex (mPFC). To characterize the effect of short-term antagonism of the D1 receptor a high-resolution autoradiographic technique was used to assess the density (Bmax) and affinity (Kd) of this receptor on pyramidal cells (i.e., large neurons (LNs, ≥100 μm2)), nonpyramidal cells (i.e., small neurons (SNs, <100 μm2)) and in the surrounding neuropil (NPL) of layer VI in rat mPFC. Either normal saline or the selective D1 antagonist SCH23390 (1.0 mg/kg/day) were administered for 48 h via Alzet osmotic pumps. Frozen sections were incubated in [3H]SCH23390 (18 nM) in the presence or absence of the competitive inhibitor SKF38393 (10 μM). A microscopic adaptation to Scatchard analysis revealed a significant increase (82%) in Bmax for neuronal cell bodies (P < 0.05), but not for neuropil of drug-treated animals. Further analysis indicated that the increase in Bmax was present on SNs (94%, P < 0.05), but not LNs in SCH23390-treated rats. In contrast, Kd values for LNs, SNs, and NPL were not significantly altered by drug treatment. Since the vast majority of SNs are nonpyramidal in nature, short-term administration of a selective D1 antagonist seems to be associated with a preferential upregulation of this receptor on interneurons. Overall, these results are consistent with the hypothesis that the mechanism of action of atypical antipsychotic medications involves changes in D1 receptor activity associated with local circuit neurons in rat mPFC. Synapse 35:173181, 2000. © 2000 Wiley-Liss, Inc. |
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